1 4872 146 OUTSIDE-IN HYPOTHESIS REVISITED: THE ROLE OF MICROBIAL, EPITHELIAL, AND IMMUNE INTERACTIONS. OBJECTIVE: OUR UNDERSTANDING OF THE ORIGIN OF ALLERGIC DISEASES HAS INCREASED IN RECENT YEARS, HIGHLIGHTING THE IMPORTANCE OF MICROBIAL DYSBIOSIS AND EPITHELIAL BARRIER DYSFUNCTION IN AFFECTED TISSUES. EXPLORING THE MICROBIAL-EPITHELIAL-IMMUNE CROSSTALK UNDERLYING THE MECHANISMS OF ALLERGIC DISEASES WILL ALLOW THE DEVELOPMENT OF NOVEL PREVENTION AND TREATMENT STRATEGIES FOR ALLERGIC DISEASES. DATA SOURCES: THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN MICROBIAL, EPITHELIAL, AND IMMUNE INTERACTIONS IN ATOPIC DERMATITIS, ALLERGIC RHINITIS, CHRONIC RHINOSINUSITIS, AND ASTHMA. STUDY SELECTIONS: WE PERFORMED A LITERATURE SEARCH, IDENTIFYING RELEVANT RECENT PRIMARY ARTICLES AND REVIEW ARTICLES. RESULTS: DYNAMIC CROSSTALK BETWEEN THE ENVIRONMENTAL FACTORS AND MICROBIAL, EPITHELIAL, AND IMMUNE CELLS IN THE DEVELOPMENT OF ATOPIC DERMATITIS, ALLERGIC RHINITIS, CHRONIC RHINOSINUSITIS, AND ASTHMA UNDERLIES THE PATHOGENESIS OF THESE DISEASES. THERE IS SUBSTANTIAL EVIDENCE IN THE LITERATURE SUGGESTING THAT ENVIRONMENTAL FACTORS DIRECTLY AFFECT BARRIER FUNCTION OF THE EPITHELIUM. IN ADDITION, T-HELPER 2 (T(H)2) CELLS, TYPE 2 INNATE LYMPHOID CELLS, AND THEIR CYTOKINE INTERLEUKIN 13 (IL-13) DAMAGE SKIN AND LUNG BARRIERS. THE EFFECTS OF ENVIRONMENTAL FACTORS MAY AT LEAST IN PART BE MEDIATED BY EPIGENETIC MECHANISMS. HISTONE DEACETYLASE ACTIVATION BY TYPE 2 IMMUNE RESPONSE HAS A MAJOR EFFECT ON LEAKY BARRIERS AND BLOCKING OF HISTONE DEACETYLASE ACTIVITY CORRECTS THE DEFECTIVE BARRIER IN HUMAN AIR-LIQUID INTERFACE CULTURES AND MOUSE MODELS OF ALLERGIC ASTHMA WITH RHINITIS. WE ALSO PRESENT AND DISCUSS A NOVEL DEVICE TO DETECT AND MONITOR SKIN BARRIER DYSFUNCTION, WHICH PROVIDES AN OPPORTUNITY TO RAPIDLY AND ROBUSTLY ASSESS DISEASE SEVERITY. CONCLUSION: A COMPLEX INTERPLAY BETWEEN ENVIRONMENTAL FACTORS, EPITHELIUM, AND THE IMMUNE SYSTEM IS INVOLVED IN THE DEVELOPMENT OF SYSTEMIC ALLERGIC DISEASES. 2020 2 5552 37 ROLE OF EPIGENETICS IN THE PATHOGENESIS OF ASTHMA. ASTHMA IS A COMPLEX, HETEROGENEOUS AND CHRONIC AIRWAY INFLAMMATORY DISEASE WITH DIFFERENT CLINICAL PHENOTYPES CAUSED BY DIVERSE TRIGGERS AND PATHOPHYSIOLOGICAL MECHANISMS. ASTHMA HERITABILITY HAS BEEN ESTABLISHED IN MANY GENETIC STUDIES BUT IT IS EVIDENT THAT ONLY GENETIC ELEMENTS ARE NOT RESPONSIBLE FOR THE DEVELOPMENT OF ASTHMA. INCREASING RATE OF ASTHMA INCIDENCE DURING PAST DECADES HAS IMPLICATED THE ROLE OF EPIGENETICS IN DEVELOPMENT OF ASTHMA. ENVIRONMENTAL FACTORS PERFORM AS INITIATOR SIGNALS THROUGH EPIGENETIC MECHANISMS. THREE EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND SMALL NONCODING RNAS. THESE MECHANISMS REGULATE THE IMMUNE RESPONSES AND INFLAMMATORY GENES EXPRESSION IN ASTHMA AND ALLERGY. THIS REVIEW EXPLAINS THE ROLE OF EPIGENETIC MODIFICATIONS IN CONTROLLING TH2 RESPONSE AND IGE PRODUCTION IN ASTHMA AND ALSO BRIEFLY OVERVIEWS THE ROLE OF ENVIRONMENTAL FACTORS SUCH AS POLLUTIONS, ALLERGENS, PRENATAL EXPOSURES AND DIET IN DEVELOPING ASTHMA. RECOGNIZING ENVIRONMENTAL RISK FACTORS AND THEIR EFFECTS ON EPIGENETIC MECHANISMS WOULD BE OF GREAT INTEREST FOR PROGNOSTIC AND PREVENTIVE ASPECT IN TREATMENT OF ASTHMA. 2017 3 2299 48 EPIGENETIC REGULATION OF AIRWAY EPITHELIUM IMMUNE FUNCTIONS IN ASTHMA. ASTHMA IS A CHRONIC INFLAMMATORY DISEASE OF THE RESPIRATORY TRACT CHARACTERIZED BY RECURRENT BREATHING PROBLEMS RESULTING FROM AIRWAY OBSTRUCTION AND HYPERRESPONSIVENESS. HUMAN AIRWAY EPITHELIUM PLAYS AN IMPORTANT ROLE IN THE INITIATION AND CONTROL OF THE IMMUNE RESPONSES TO DIFFERENT TYPES OF ENVIRONMENTAL FACTORS CONTRIBUTING TO ASTHMA PATHOGENESIS. USING PATTERN RECOGNITION RECEPTORS AIRWAY EPITHELIUM SENSES EXTERNAL STIMULI, SUCH AS ALLERGENS, MICROBES, OR POLLUTANTS, AND SUBSEQUENTLY SECRETES ENDOGENOUS DANGER SIGNALING MOLECULES ALARMING AND ACTIVATING DENDRITIC CELLS. HENCE, AIRWAY EPITHELIAL CELLS NOT ONLY MEDIATE INNATE IMMUNE RESPONSES BUT ALSO BRIDGE THEM WITH ADAPTIVE IMMUNE RESPONSES INVOLVING T AND B CELLS THAT PLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF ASTHMA. THE EFFECTS OF ENVIRONMENTAL FACTORS ON THE DEVELOPMENT OF ASTHMA ARE MEDIATED, AT LEAST IN PART, BY EPIGENETIC MECHANISMS. THOSE COMPRISE CLASSICAL EPIGENETICS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS AFFECTING TRANSCRIPTION, AS WELL AS MICRORNAS INFLUENCING TRANSLATION. THE COMMON FEATURE OF SUCH MECHANISMS IS THAT THEY REGULATE GENE EXPRESSION WITHOUT AFFECTING THE NUCLEOTIDE SEQUENCE OF THE GENOMIC DNA. EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE IN THE REGULATION OF DIFFERENT CELL POPULATIONS INVOLVED IN ASTHMA PATHOGENESIS, WITH THE REMARKABLE EXAMPLE OF T CELLS. RECENTLY, HOWEVER, THERE IS INCREASING EVIDENCE THAT EPIGENETIC MECHANISMS ARE ALSO CRUCIAL FOR THE REGULATION OF AIRWAY EPITHELIAL CELLS, ESPECIALLY IN THE CONTEXT OF EPIGENETIC TRANSFER OF ENVIRONMENTAL EFFECTS CONTRIBUTING TO ASTHMA PATHOGENESIS. IN THIS REVIEW, WE SUMMARIZE THE ACCUMULATING EVIDENCE FOR THIS VERY IMPORTANT ASPECT OF AIRWAY EPITHELIAL CELL PATHOBIOLOGY. 2020 4 1606 41 DNA METHYLATION, BACTERIA AND AIRWAY INFLAMMATION: LATEST INSIGHTS. PURPOSE OF REVIEW: DNA METHYLATION IS AN EPIGENETIC MECHANISM THAT HAS BEEN IMPLICATED IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES BY REGULATING DIFFERENTIATION, PROLIFERATION, APOPTOSIS, AND ACTIVATION OF IMMUNE CELLS. CHANGES IN THE METHYLATION STATUS OF RELEVANT GENES HAVE BEEN LINKED TO THE ORIGIN, PERPETUATION, AND SEVERITY OF AIRWAY DISEASES. THE DNA METHYLATION PROFILE CAN BE ALSO MODIFIED BY THE ACTION OF VIRAL AND BACTERIAL COLONIZATION. BACTERIA AND SPECIALLY STAPHYLOCOCCUS AUREUS TOXINS ARE RECOGNIZED INFLAMMATORY AMPLIFYING FACTORS IN BOTH LOWER AND UPPER AIRWAY CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE EXISTENT KNOWLEDGE ABOUT THE ROLE OF DNA METHYLATION CHANGES IN CHRONIC AIRWAY DISEASES AND THE CONTRIBUTION OF BACTERIAL INFECTION ON THIS EVENT. RECENT FINDINGS: IT HAS BEEN DEMONSTRATED THAT CHANGES IN DNA METHYLATION, EITHER INTRINSIC OR INDUCED BY ALLERGEN OR INFECTION, MAY BE LINKED TO THE PATHOGENESIS OF ASTHMA AND ALLERGY. THESE CHANGES IN METHYLATION MAY SUPPRESS THE PRODUCTION OF ANTI-INFLAMMATORY MEDIATORS AND INCREASE THE SURVIVAL AND ACTIVATION OF PRO-INFLAMMATORY CELLS, AS WELL AS MODIFY THE IMMUNE RESPONSE IN RESPONSE TO BACTERIAL INFECTION, INCREASING THEIR SURVIVAL AND PATHOGENICITY WITHIN THE INFECTED ORGANISM. SUMMARY: UNDERSTANDING THE INTRINSIC EPIGENETIC MECHANISMS, AS WELL AS THE EFFECT OF ENVIRONMENT -FOR EXAMPLE, BACTERIAL INFECTION IN THE PATHOGENESIS OF AIRWAYS DISEASES - WILL GREATLY IMPROVE THE MANAGEMENT AND THE DIAGNOSIS OF THESE DISEASES. 2015 5 874 33 CHRONIC ALLERGY SIGNALING: IS IT ALL STRESSED-OUT MITOCHONDRIA? ALLERGIC DISEASES IN GENERAL, AND CHRONIC ALLERGIC INFLAMMATION IN PARTICULAR, ARE ON THE RISE IN THE UNITED STATES AND OTHER DEVELOPED COUNTRIES. THE IDEA OF CHRONIC ALLERGIC DISEASE AS A CHRONIC TYPE 2 IMMUNE RESPONSE HAS BEEN AROUND FOR SEVERAL DECADES. HOWEVER, DATA SUGGEST THAT OTHER MECHANISMS MAY BE IMPORTANT IN CHRONIC DISEASE. THEREFORE, WE BELIEVE IT IS TIME FOR A PARADIGM SHIFT IN UNDERSTANDING THE MECHANISTIC CAUSES OF DISEASE SYMPTOMS IN THESE DISEASES. IN THIS REVIEW, WE HAVE AVOIDED THE CLASSIC CANONICAL PATHWAYS AND FOCUSED ON THE EMERGING IDEA THAT OXIDATIVE STRESS, CHANGES IN IMMUNO-METABOLISM, MITOCHONDRIAL DYSFUNCTION, AND EPIGENETIC CHANGES (PARTICULARLY MICRORNA PROFILE) MAY BE WORKING CONCURRENTLY OR SYNERGISTICALLY TO POTENTIATE ALLERGIC DISEASE SYMPTOMS. FURTHERMORE, WE HAVE ADDRESSED HOW THE EPIDEMIC OF OBESITY EXACERBATES ALLERGIC DISEASE VIA THE DYSREGULATION OF THE AFOREMENTIONED FACTORS. 2022 6 2330 37 EPIGENETIC REGULATION OF IMMUNE FUNCTION IN ASTHMA. ASTHMA IS A COMMON COMPLEX RESPIRATORY DISEASE CHARACTERIZED BY CHRONIC AIRWAY INFLAMMATION AND PARTIALLY REVERSIBLE AIRFLOW OBSTRUCTION RESULTING FROM GENETIC AND ENVIRONMENTAL DETERMINANTS. BECAUSE EPIGENETIC MARKS INFLUENCE GENE EXPRESSION AND CAN BE MODIFIED BY BOTH ENVIRONMENTAL EXPOSURES AND GENETIC VARIATION, THEY ARE INCREASINGLY RECOGNIZED AS RELEVANT TO THE PATHOGENESIS OF ASTHMA AND MAY BE A KEY LINK BETWEEN ENVIRONMENTAL EXPOSURES AND ASTHMA SUSCEPTIBILITY. UNLIKE CHANGES TO DNA SEQUENCE, EPIGENETIC SIGNATURES ARE DYNAMIC AND REVERSIBLE, CREATING AN OPPORTUNITY FOR NOT ONLY THERAPEUTIC TARGETS BUT MAY SERVE AS BIOMARKERS TO FOLLOW DISEASE COURSE AND IDENTIFY MOLECULAR SUBTYPES IN HETEROGENEOUS DISEASES SUCH AS ASTHMA. IN THIS REVIEW, WE WILL EXAMINE THE RELATIONSHIP BETWEEN ASTHMA AND 3 KEY EPIGENETIC PROCESSES THAT MODIFY GENE EXPRESSION: DNA METHYLATION, MODIFICATION OF HISTONE TAILS, AND NONCODING RNAS. IN ADDITION TO PRESENTING A COMPREHENSIVE ASSESSMENT OF THE EXISTING EPIGENETIC STUDIES FOCUSING ON IMMUNE REGULATION IN ASTHMA, WE WILL DISCUSS FUTURE DIRECTIONS FOR EPIGENETIC INVESTIGATION IN ALLERGIC AIRWAY DISEASE. 2022 7 6735 39 WHAT HAVE MECHANISTIC STUDIES TAUGHT US ABOUT CHILDHOOD ASTHMA? CHILDHOOD ASTHMA IS A CHRONIC HETEROGENEOUS SYNDROME CONSISTING OF DIFFERENT DISEASE ENTITIES OR PHENOTYPES. THE IMMUNOLOGIC AND CELLULAR PROCESSES THAT OCCUR DURING ASTHMA DEVELOPMENT ARE STILL NOT FULLY UNDERSTOOD BUT REPRESENT DISTINCT ENDOTYPES. MECHANISTIC STUDIES HAVE EXAMINED THE ROLE OF GENE EXPRESSION, PROTEIN LEVELS, AND CELL TYPES IN EARLY LIFE DEVELOPMENT AND THE MANIFESTATION OF ASTHMA, MANY UNDER THE INFLUENCE OF ENVIRONMENTAL STIMULI, WHICH CAN BE BOTH PROTECTIVE AND RISK FACTORS FOR ASTHMA. GENETIC VARIANTS CAN REGULATE GENE EXPRESSION, CONTROLLED PARTLY BY DIFFERENT EPIGENETIC MECHANISMS. IN ADDITION, ENVIRONMENTAL FACTORS, SUCH AS LIVING SPACE, NUTRITION, AND SMOKING, CAN CONTRIBUTE TO THESE MECHANISMS. ALL OF THESE FACTORS PRODUCE MODIFICATIONS IN GENE EXPRESSION THAT CAN ALTER THE DEVELOPMENT AND FUNCTION OF IMMUNE AND EPITHELIAL CELLS AND SUBSEQUENTLY DIFFERENT TRAJECTORIES OF CHILDHOOD ASTHMA. THESE EARLY CHANGES IN A PARTIALLY IMMATURE IMMUNE SYSTEM CAN HAVE DRAMATIC EFFECTS (E.G., CAUSING DYSREGULATION), WHICH IN TURN CONTRIBUTE TO DIFFERENT DISEASE ENDOTYPES AND MAY HELP TO EXPLAIN DIFFERENTIAL RESPONSIVENESS TO ASTHMA TREATMENT. IN THIS REVIEW, WE SUMMARIZE PUBLISHED STUDIES THAT HAVE AIMED TO UNCOVER DISTINCT MECHANISMS IN CHILDHOOD ASTHMA, CONSIDERING GENETICS, EPIGENETICS, AND ENVIRONMENT. MOREOVER, A DISCUSSION OF NEW, POWERFUL TOOLS FOR SINGLE-CELL IMMUNOLOGIC ASSAYS FOR PHENOTYPIC AND FUNCTIONAL ANALYSIS IS INCLUDED, WHICH PROMISE NEW MECHANISTIC INSIGHTS INTO CHILDHOOD ASTHMA DEVELOPMENT AND THERAPEUTIC AND PREVENTIVE STRATEGIES. 2023 8 4273 41 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023 9 5472 46 RESPIRATORY VIRAL INFECTIONS IN EXACERBATION OF CHRONIC AIRWAY INFLAMMATORY DISEASES: NOVEL MECHANISMS AND INSIGHTS FROM THE UPPER AIRWAY EPITHELIUM. RESPIRATORY VIRUS INFECTION IS ONE OF THE MAJOR SOURCES OF EXACERBATION OF CHRONIC AIRWAY INFLAMMATORY DISEASES. THESE EXACERBATIONS ARE ASSOCIATED WITH HIGH MORBIDITY AND EVEN MORTALITY WORLDWIDE. THE CURRENT UNDERSTANDING ON VIRAL-INDUCED EXACERBATIONS IS THAT VIRAL INFECTION INCREASES AIRWAY INFLAMMATION WHICH AGGRAVATES DISEASE SYMPTOMS. RECENT ADVANCES IN IN VITRO AIR-LIQUID INTERFACE 3D CULTURES, ORGANOID CULTURES AND THE USE OF NOVEL HUMAN AND ANIMAL CHALLENGE MODELS HAVE EVOKED NEW UNDERSTANDINGS AS TO THE MECHANISMS OF VIRAL EXACERBATIONS. IN THIS REVIEW, WE WILL FOCUS ON RECENT NOVEL FINDINGS THAT ELUCIDATE HOW RESPIRATORY VIRAL INFECTIONS ALTER THE EPITHELIAL BARRIER IN THE AIRWAYS, THE UPPER AIRWAY MICROBIAL ENVIRONMENT, EPIGENETIC MODIFICATIONS INCLUDING MIRNA MODULATION, AND OTHER CHANGES IN IMMUNE RESPONSES THROUGHOUT THE UPPER AND LOWER AIRWAYS. FIRST, WE REVIEWED THE PREVALENCE OF DIFFERENT RESPIRATORY VIRAL INFECTIONS IN CAUSING EXACERBATIONS IN CHRONIC AIRWAY INFLAMMATORY DISEASES. SUBSEQUENTLY WE ALSO SUMMARIZED HOW RECENT MODELS HAVE EXPANDED OUR APPRECIATION OF THE MECHANISMS OF VIRAL-INDUCED EXACERBATIONS. FURTHER WE HIGHLIGHTED THE IMPORTANCE OF THE VIROME WITHIN THE AIRWAY MICROBIOME ENVIRONMENT AND ITS IMPACT ON SUBSEQUENT BACTERIAL INFECTION. THIS REVIEW CONSOLIDATES THE UNDERSTANDING OF VIRAL INDUCED EXACERBATION IN CHRONIC AIRWAY INFLAMMATORY DISEASES AND INDICATES PATHWAYS THAT MAY BE TARGETED FOR MORE EFFECTIVE MANAGEMENT OF CHRONIC INFLAMMATORY DISEASES. 2020 10 3421 43 HUMAN MATTERS IN ASTHMA: CONSIDERING THE MICROBIOME IN PULMONARY HEALTH. MICROBIAL COMMUNITIES FORM AN IMPORTANT SYMBIOTIC ECOSYSTEM WITHIN HUMANS AND HAVE DIRECT EFFECTS ON HEALTH AND WELL-BEING. NUMEROUS EXOGENOUS FACTORS INCLUDING AIRBORNE TRIGGERS, DIET, AND DRUGS IMPACT THESE ESTABLISHED, BUT FRAGILE COMMUNITIES ACROSS THE HUMAN LIFESPAN. CROSSTALK BETWEEN THE MUCOSAL MICROBIOTA AND THE IMMUNE SYSTEM AS WELL AS THE GUT-LUNG AXIS HAVE DIRECT CORRELATIONS TO IMMUNE BIAS THAT MAY PROMOTE CHRONIC DISEASES LIKE ASTHMA. ASTHMA INITIATION AND PATHOGENESIS ARE MULTIFACETED AND COMPLEX WITH INPUT FROM GENETIC, EPIGENETIC, AND ENVIRONMENTAL COMPONENTS. IN THIS REVIEW, WE SUMMARIZE AND DISCUSS THE ROLE OF THE AIRWAY MICROBIOME IN ASTHMA, AND HOW THE ENVIRONMENT, DIET AND THERAPEUTICS IMPACT THIS LOW BIOMASS COMMUNITY OF MICROORGANISMS. WE ALSO FOCUS THIS REVIEW ON THE PEDIATRIC AND BLACK POPULATIONS AS HIGH-RISK GROUPS REQUIRING SPECIAL ATTENTION, EMPHASIZING THAT THE WHOLE PATIENT MUST BE CONSIDERED DURING TREATMENT. ALTHOUGH NEW CULTURE-INDEPENDENT TECHNIQUES HAVE BEEN DEVELOPED AND ARE MORE ACCESSIBLE TO RESEARCHERS, THE EXACT CONTRIBUTION THE AIRWAY MICROBIOME MAKES IN ASTHMA PATHOGENESIS IS NOT WELL UNDERSTOOD. UNDERSTANDING HOW THE AIRWAY MICROBIOME, AS A LIVING ENTITY IN THE RESPIRATORY TRACT, PARTICIPATES IN LUNG IMMUNITY DURING THE DEVELOPMENT AND PROGRESSION OF ASTHMA MAY LEAD TO CRITICAL NEW TREATMENTS FOR ASTHMA, INCLUDING POPULATION-TARGETED INTERVENTIONS, OR EVEN MORE EFFECTIVE ADMINISTRATION OF CURRENTLY AVAILABLE THERAPEUTICS. 2022 11 5031 42 PERSPECTIVES ON THE ETIOLOGY OF CHRONIC RHINOSINUSITIS: AN IMMUNE BARRIER HYPOTHESIS. BACKGROUND: CHRONIC RHINOSINUSITIS (CRS) HAS BEEN DEFINED AS PERSISTENT SYMPTOMATIC INFLAMMATION OF THE NASAL AND SINUS MUCOSA RESULTING FROM THE INTERACTION OF MULTIPLE HOST AND ENVIRONMENTAL FACTORS. RECENT STUDIES HAVE IMPLICATED ALTERNARIA FUNGI OR TOXIGENIC STAPHYLOCOCCUS AUREUS AS CRITICAL AGENTS IN CRS PATHOGENESIS. THE EMPHASIS ON ENVIRONMENTAL AGENTS IN CRS ETIOLOGY HAS FOCUSED INTEREST TOWARD ELIMINATION OF THOSE AGENTS AS THE PRIME MECHANISM OF THERAPY. THIS VIEWPOINT IS IN MARKED CONTRAST TO THE CURRENT PERSPECTIVE ON SOME OTHER CHRONIC INFLAMMATORY EPITHELIAL DISORDERS THAT AFFLICT THE SKIN, LUNGS, AND GUT, WHEREIN HOST FACTORS ARE BELIEVED TO PREDISPOSE TO DISEASE EXPRESSION IN THE PRESENCE OF UBIQUITOUS ENVIRONMENTAL AGENTS. METHODS: THE CURRENT REVIEW EVALUATES CRS ETIOLOGY FROM THIS PERSPECTIVE AND CONSIDERS THAT CRS DEVELOPS, IN PART, AS AN OUTCOME OF A DYSFUNCTIONAL HOST RESPONSE. SPECIFICALLY, EVIDENCE FROM OUR LABORATORY AND OTHERS WILL BE REVIEWED INDICATING THAT CRS IS ASSOCIATED WITH A FAILURE OF THE MECHANICAL AND IMMUNOLOGIC BARRIERS ACROSS THE NASAL MUCOSA. THE HYPOTHESIS WOULD FURTHER PROPOSE THAT GENETIC AND EPIGENETIC VARIATION PREDISPOSES SUSCEPTIBLE INDIVIDUALS TO BARRIER FAILURE IN THE PRESENCE OF ENVIRONMENTAL STRESS LEADING TO CRS. RESULTS: FROM THIS UNIFYING PERSPECTIVE, BACTERIA AND FUNGI ARE SEEN AS DISEASE MODIFIERS RATHER THAN PRIMARY ETIOLOGIC AGENTS. CONCLUSION: THE GOAL IS TO PLACE CONCEPTS OF CRS PATHOPHYSIOLOGY IN A FRAMEWORK CONSISTENT WITH A CURRENT UNDERSTANDING OF CHRONIC INFLAMMATION IN GENERAL AND EPITHELIAL DISEASE IN PARTICULAR. 2008 12 6288 43 THE POTENTIAL ROLE OF EPIGENETIC MODIFICATIONS ON DIFFERENT FACETS IN THE PERIODONTAL PATHOGENESIS. PERIODONTITIS IS A CHRONIC INFLAMMATORY DISEASE THAT AFFECTS THE SUPPORTING STRUCTURES OF TEETH. IN THE LITERATURE, THE ASSOCIATION BETWEEN THE PATHOGENICITY OF BACTERIA AND ENVIRONMENTAL FACTORS IN THIS REGARD HAVE BEEN EXTENSIVELY EXAMINED. IN THE PRESENT STUDY, WE WILL SHED LIGHT ON THE POTENTIAL ROLE THAT EPIGENETIC CHANGE CAN PLAY ON DIFFERENT FACETS OF ITS PROCESS, MORE PARTICULARLY THE MODIFICATIONS CONCERNING THE GENES INVOLVED IN INFLAMMATION, DEFENSE, AND IMMUNE SYSTEMS. SINCE THE 1960S, THE ROLE OF GENETIC VARIANTS IN THE ONSET AND SEVERITY OF PERIODONTAL DISEASE HAS BEEN WIDELY DEMONSTRATED. THESE MAKE SOME PEOPLE MORE SUSCEPTIBLE TO DEVELOPING IT THAN OTHERS. IT HAS BEEN DOCUMENTED THAT THE WIDE VARIATION IN ITS FREQUENCY FOR VARIOUS RACIAL AND ETHNIC POPULATIONS IS DUE PRIMARILY TO THE COMPLEX INTERPLAY AMONG GENETIC FACTORS WITH THOSE AFFECTING THE ENVIRONMENT AND THE DEMOGRAPHY. IN MOLECULAR BIOLOGY, EPIGENETIC MODIFICATIONS ARE DEFINED AS ANY CHANGE IN THE PROMOTER FOR THE CPG ISLANDS, IN THE STRUCTURE OF THE HISTONE PROTEIN, AS WELL AS POST-TRANSLATIONAL REGULATION BY MICRORNAS (MIRNAS), BEING KNOWN TO CONTRIBUTE TO THE ALTERATION IN GENE EXPRESSION FOR COMPLEX MULTIFACTORIAL DISEASES SUCH AS PERIODONTITIS. THE KEY ROLE OF EPIGENETIC MODIFICATION IS TO UNDERSTAND THE MECHANISM INVOLVED IN THE GENE-ENVIRONMENT INTERACTION, AND THE DEVELOPMENT OF PERIODONTITIS IS NOW THE SUBJECT OF MORE AND MORE STUDIES THAT ATTEMPT TO IDENTIFY WHICH FACTORS ARE STIMULATING IT, BUT ALSO AFFECT THE REDUCED RESPONSE TO THERAPY. 2023 13 6005 43 THE AIRWAY EPITHELIUM-A CENTRAL PLAYER IN ASTHMA PATHOGENESIS. ASTHMA IS A CHRONIC INFLAMMATORY AIRWAY DISEASE CHARACTERIZED BY VARIABLE AIRFLOW OBSTRUCTION IN RESPONSE TO A WIDE RANGE OF EXOGENOUS STIMULI. THE AIRWAY EPITHELIUM IS THE FIRST LINE OF DEFENSE AND PLAYS AN IMPORTANT ROLE IN INITIATING HOST DEFENSE AND CONTROLLING IMMUNE RESPONSES. INDEED, INCREASING EVIDENCE INDICATES A RANGE OF ABNORMALITIES IN VARIOUS ASPECTS OF EPITHELIAL BARRIER FUNCTION IN ASTHMA. A CENTRAL PART OF THIS IMPAIRMENT IS A DISRUPTION OF THE AIRWAY EPITHELIAL LAYER, ALLOWING INHALED SUBSTANCES TO PASS MORE EASILY INTO THE SUBMUCOSA WHERE THEY MAY INTERACT WITH IMMUNE CELLS. FURTHERMORE, MANY OF THE IDENTIFIED SUSCEPTIBILITY GENES FOR ASTHMA ARE EXPRESSED IN THE AIRWAY EPITHELIUM. THIS REVIEW FOCUSES ON THE BIOLOGY OF THE AIRWAY EPITHELIUM IN HEALTH AND ITS PATHOBIOLOGY IN ASTHMA. WE WILL SPECIFICALLY DISCUSS EXTERNAL TRIGGERS SUCH AS ALLERGENS, VIRUSES AND ALARMINS AND THE EFFECT OF TYPE 2 INFLAMMATORY RESPONSES ON AIRWAY EPITHELIAL FUNCTION IN ASTHMA. WE WILL ALSO DISCUSS EPIGENETIC MECHANISMS RESPONDING TO EXTERNAL STIMULI ON THE LEVEL OF TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION OF GENE EXPRESSION, AS WELL THE AIRWAY EPITHELIUM AS A POTENTIAL TREATMENT TARGET IN ASTHMA. 2020 14 5534 32 ROLE OF AIRWAY EPITHELIAL CELLS IN THE DEVELOPMENT OF DIFFERENT ASTHMA PHENOTYPES. THE TERM (BRONCHIAL) ASTHMA DESCRIBES A DISORDER SYNDROME THAT COMPRISES SEVERAL DISEASE PHENOTYPES, ALL CHARACTERIZED BY CHRONIC INFLAMMATION IN THE BRONCHIAL EPITHELIUM, WITH A VARIETY OF SUBSEQUENT FUNCTIONAL CONSEQUENCES. THUS, THE EPITHELIUM IN THE CONDUCTING AIRWAYS IS THE MAIN LOCALIZATION OF THE COMPLEX PATHOLOGICAL CHANGES IN THE DISEASE. IN THIS REGARD, BRONCHIAL EPITHELIAL CELLS ARE NOT PASSIVELY AFFECTED BY INFLAMMATORY MECHANISMS INDUCED BY IMMUNOLOGICAL PROCESSES BUT RATHER ACTIVELY INVOLVED IN ALL STEPS OF DISEASE DEVELOPMENT FROM INITIATION AND PERPETUATION TO CHRONIFICATION. IN RECENT YEARS IT TURNED OUT THAT BRONCHIAL EPITHELIAL CELLS SHOW A HIGH LEVEL OF STRUCTURAL AND FUNCTIONAL DIVERSITY AND PLASTICITY WITH EPIGENETIC MECHANISMS PLAYING A CRUCIAL ROLE IN THE REGULATION OF THESE PROCESSES. THUS, IT IS QUITE REASONABLE THAT DIFFERENTIAL FUNCTIONAL ACTIVITIES OF THE BRONCHIAL EPITHELIUM ARE INVOLVED IN THE DEVELOPMENT OF DIFFERENT ASTHMA PHENOTYPES AND/OR STAGES OF DISEASE. THE CURRENT KNOWLEDGE ON THIS TOPIC WILL BE DISCUSSED IN THIS REVIEW ARTICLE. 2020 15 3681 38 INFLAMMATION, DNA METHYLATION AND COLITIS-ASSOCIATED CANCER. INFLAMMATION CAN RESULT FROM A RANGE OF SOURCES INCLUDING MICROBIAL INFECTIONS, EXPOSURE TO ALLERGENS AND TOXIC CHEMICALS, AUTOIMMUNE DISEASE AND OBESITY. A WELL-BALANCED IMMUNE RESPONSE CAN BE ANTI-TUMORIGENIC; HOWEVER, A SUSTAINED OR CHRONIC INFLAMMATORY RESPONSE IS GENERALLY HARMFUL AS THE IMMUNE RESPONSE BECOMES DISTORTED. A CAUSAL LINK BETWEEN CHRONIC INFLAMMATION AND CANCER IS NOW WELL ACCEPTED AND MANY CHRONICALLY INFLAMED ORGANS OF THE GASTROINTESTINAL TRACT SHOW THIS ASSOCIATION. FOR EXAMPLE, PATIENTS WITH INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING BOTH ULCERATIVE COLITIS AND CROHN'S DISEASE, HAVE A 2- TO 3-FOLD GREATER LIFETIME RISK OF DEVELOPING COLORECTAL CANCER COMPARED WITH THE GENERAL POPULATION. THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER (CAC) IS THOUGHT TO BE MULTIFACETED AND IS PROBABLY DUE TO A COMBINATION OF GENETIC FACTORS, EPIGENETIC FACTORS AND THE DURATION, EXTENT AND SEVERITY OF DISEASE. RECENTLY, EPIGENETIC ALTERATIONS, IN PARTICULAR ALTERATIONS IN DNA METHYLATION, HAVE BEEN OBSERVED DURING INFLAMMATION AND INFLAMMATION-ASSOCIATED CARCINOGENESIS. THE MEDIATORS OF THIS, THE SIGNIFICANCE OF THESE CHANGES IN DNA METHYLATION AND THE EFFECT THIS HAS ON GENE EXPRESSION AND THE MALIGNANT TRANSFORMATION OF THE EPITHELIAL CELLS DURING IBD AND CAC ARE DISCUSSED IN THIS REVIEW. THE RECENT ADVANCES IN TECHNOLOGIES TO STUDY GENOME-WIDE DNA METHYLATION AND THE THERAPEUTIC POTENTIAL OF UNDERSTANDING THESE MOLECULAR MECHANISMS ARE ALSO HIGHLIGHTED. 2012 16 2333 33 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 17 3104 35 GENOMIC, EPIGENOMIC, TRANSCRIPTOMIC, PROTEOMIC AND METABOLOMIC APPROACHES IN ATOPIC DERMATITIS. ATOPIC DERMATITIS (AD) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH A HIGH PREVALENCE IN THE DEVELOPED COUNTRIES. IT IS ASSOCIATED WITH ATOPIC AND NON-ATOPIC DISEASES, AND ITS CLOSE CORRELATION WITH ATOPIC COMORBIDITIES HAS BEEN GENETICALLY DEMONSTRATED. ONE OF THE MAIN ROLES OF GENETIC STUDIES IS TO COMPREHEND THE DEFECTS OF THE CUTANEOUS BARRIER DUE TO FILAGGRIN DEFICIT AND EPIDERMAL SPONGIOSIS. RECENTLY, EPIGENETIC STUDIES STARTED TO ANALYZE THE INFLUENCE OF THE ENVIRONMENTAL FACTORS ON GENE EXPRESSION. THE EPIGENOME IS CONSIDERED TO BE A SUPERIOR SECOND CODE THAT CONTROLS THE GENOME, WHICH INCLUDES ALTERATIONS OF THE CHROMATIN. THE EPIGENETIC CHANGES DO NOT ALTER THE GENETIC CODE, HOWEVER, CHANGES IN THE CHROMATIN STRUCTURE COULD ACTIVATE OR INHIBIT THE TRANSCRIPTION PROCESS OF CERTAIN GENES AND CONSEQUENTLY, THE TRANSLATION PROCESS OF THE NEW MRNA INTO A POLYPEPTIDE CHAIN. IN-DEPTH ANALYSIS OF THE TRANSCRIPTOMIC, METABOLOMIC AND PROTEOMIC STUDIES ALLOW TO UNRAVEL DETAILED MECHANISMS THAT CAUSE AD. THE EXTRACELLULAR SPACE AND LIPID METABOLISM ARE ASSOCIATED WITH AD THAT IS INDEPENDENT OF THE FILAGGRIN EXPRESSION. ON THE OTHER HAND, AROUND 45 PROTEINS ARE CONSIDERED AS THE PRINCIPAL COMPONENTS IN THE ATOPIC SKIN. MOREOVER, GENETIC STUDIES BASED ON THE DISRUPTED CUTANEOUS BARRIER CAN LEAD TO THE DEVELOPMENT OF NEW TREATMENTS TARGETING THE CUTANEOUS BARRIER OR CUTANEOUS INFLAMMATION. UNFORTUNATELY, AT PRESENT, THERE ARE NO TARGET THERAPIES THAT FOCUS ON THE EPIGENETIC PROCESS OF AD. HOWEVER, IN THE FUTURE, MIR-143 COULD BE AN IMPORTANT OBJECTIVE FOR NEW THERAPIES, AS IT TARGETS THE MIR-335:SOX AXIS, THEREBY RESTORING THE MIR-335 EXPRESSION, AND REPAIRING THE CUTANEOUS BARRIER DEFECTS. 2023 18 2531 37 EPIGENETICS IN ASTHMA. PURPOSE OF REVIEW: ASTHMA IS ONE OF THE MOST COMMON CHRONIC RESPIRATORY DISEASES LINKED WITH INCREASED MORBIDITY AND HEALTHCARE UTILIZATION. THE UNDERLYING PATHOPHYSIOLOGICAL PROCESSES AND CAUSAL RELATIONSHIPS OF ASTHMA WITH EPIGENETIC MECHANISMS ARE PARTIALLY UNDERSTOOD. HERE WE REVIEW HUMAN STUDIES OF EPIGENETIC MECHANISMS IN ASTHMA, WITH A SPECIAL FOCUS ON DNA METHYLATION. RECENT FINDINGS: EPIGENETIC STUDIES OF CHILDHOOD ASTHMA HAVE IDENTIFIED SPECIFIC METHYLATION SIGNATURES ASSOCIATED WITH ALLERGIC INFLAMMATION IN THE AIRWAY AND IMMUNE CELLS, DEMONSTRATING A REGULATORY ROLE FOR METHYLATION IN ASTHMA PATHOGENESIS. DESPITE THESE NOVEL FINDINGS, ADDITIONAL RESEARCH IN THE ROLE OF EPIGENETIC MECHANISMS UNDERLYING ASTHMA ENDOTYPES IS NEEDED. SIMILARLY, STUDIES OF HISTONE MODIFICATIONS ARE ALSO LACKING IN ASTHMA. FUTURE STUDIES OF EPIGENETIC MECHANISMS IN ASTHMA WILL BENEFIT FROM DATA INTEGRATION IN WELL PHENOTYPED COHORTS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CURRENT LITERATURE ON EPIGENETIC STUDIES IN HUMAN ASTHMA, WITH SPECIAL EMPHASIS ON METHYLATION AND CHILDHOOD ASTHMA. 2019 19 2519 43 EPIGENETICS AND THE ENVIRONMENT IN AIRWAY DISEASE: ASTHMA AND ALLERGIC RHINITIS. ASTHMA AND RHINITIS ARE COMPLEX, HETEROGENEOUS DISEASES CHARACTERIZED BY CHRONIC INFLAMMATION OF THE UPPER AND LOWER AIRWAYS. WHILE GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED A NUMBER OF SUSCEPTIBLE LOCI AND CANDIDATE GENES ASSOCIATED WITH THE PATHOGENESIS OF ASTHMA AND ALLERGIC RHINITIS (AR), THE RISK-ASSOCIATED ALLELES ACCOUNT FOR ONLY A VERY SMALL PERCENT OF THE GENETIC RISK. IN ALLERGIC AIRWAY AND OTHER COMPLEX DISEASES, IT IS THOUGHT THAT EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING MICRORNAS, CAUSED BY COMPLEX INTERACTIONS BETWEEN THE UNDERLYING GENOME AND THE ENVIRONMENT MAY ACCOUNT FOR SOME OF THIS "MISSING HERITABILITY" AND MAY EXPLAIN THE HIGH DEGREE OF PLASTICITY IN IMMUNE RESPONSES. IN THIS CHAPTER, WE WILL FOCUS ON THE CURRENT KNOWLEDGE OF CLASSICAL EPIGENETIC MODIFICATIONS, DNA METHYLATION AND HISTONE MODIFICATIONS, AND THEIR POTENTIAL ROLE IN ASTHMA AND AR. IN PARTICULAR, WE WILL REVIEW EPIGENETIC VARIATIONS ASSOCIATED WITH MATERNAL AIRWAY DISEASE, DEMOGRAPHICS, ENVIRONMENT, AND NON-SPECIFIC ASSOCIATIONS. THE ROLE OF SPECIFIC GENETIC HAPLOTYPES IN ENVIRONMENTALLY INDUCED EPIGENETIC CHANGES ARE ALSO DISCUSSED. A MAJOR LIMITATION OF MANY OF THE CURRENT STUDIES OF ASTHMA EPIGENETICS IS THAT THEY EVALUATE EPIGENETIC MODIFICATIONS IN BOTH ALLERGIC AND NON-ALLERGIC ASTHMA, MAKING IT DIFFICULT TO DISTINGUISH THOSE EPIGENETIC MODIFICATIONS THAT MEDIATE ALLERGIC ASTHMA FROM THOSE THAT MEDIATE NON-ALLERGIC ASTHMA. ADDITIONALLY, MOST DNA METHYLATION STUDIES IN ASTHMA USE PERIPHERAL OR CORD BLOOD DUE TO POOR ACCESSIBILITY OF AIRWAY CELLS OR TISSUE. UNLIKE DNA SEQUENCES, EPIGENETIC ALTERATIONS ARE QUITE CELL- AND TISSUE-SPECIFIC, AND EPIGENETIC CHANGES FOUND IN AIRWAY TISSUE OR CELLS MAY BE DISCORDANT FROM THAT OF CIRCULATING BLOOD. THESE TWO CONFOUNDING FACTORS SHOULD BE CONSIDERED WHEN REVIEWING EPIGENETIC STUDIES IN ALLERGIC AIRWAY DISEASE. 2020 20 3402 38 HOW DOES AGE DETERMINE THE DEVELOPMENT OF HUMAN IMMUNE-MEDIATED ARTHRITIS? DOES AGE SUBSTANTIALLY AFFECT THE EMERGENCE OF HUMAN IMMUNE-MEDIATED ARTHRITIS? CHILDREN DO NOT USUALLY DEVELOP IMMUNE-MEDIATED ARTICULAR INFLAMMATION DURING THEIR FIRST YEAR OF LIFE. IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS, THIS APPARENT 'IMMUNE PRIVILEGE' DISINTEGRATES, AND CHRONIC INFLAMMATION IS ASSOCIATED WITH VARIABLE AUTOANTIBODY SIGNATURES AND PATTERNS OF DISEASE THAT RESEMBLE ADULT ARTHRITIS PHENOTYPES. NUMEROUS MECHANISMS MIGHT BE INVOLVED IN THIS SHIFT, INCLUDING GENETIC AND EPIGENETIC PREDISPOSING FACTORS, MATURATION OF THE IMMUNE SYSTEM WITH A PROGRESSIVE MODULATION OF PUTATIVE TOLEROGENIC CONTROLS, PARALLEL DEVELOPMENT OF MICROBIAL DYSBIOSIS, ACCUMULATION OF A PRO-INFLAMMATORY BURDEN DRIVEN BY ENVIRONMENTAL EXPOSURES (THE EXPOSOME) AND COMORBIDITY-RELATED DRIVERS. BY EXPLORING THESE MECHANISMS, WE EXPAND THE DISCUSSION OF THREE (NOT MUTUALLY EXCLUSIVE) HYPOTHESES ON HOW THESE FACTORS CAN CONTRIBUTE TO THE DIFFERENCES AND SIMILARITIES BETWEEN THE LOSS OF IMMUNE TOLERANCE IN CHILDREN AND THE DEVELOPMENT OF ESTABLISHED IMMUNE-MEDIATED ARTHRITIS IN ADULTS. THESE THREE HYPOTHESES RELATE TO A CRITICAL WINDOW IN GENETICS AND EPIGENETICS, IMMUNE MATURATION, AND THE ACCUMULATION OF BURDEN. THE VARIED MANIFESTATION OF THE UNDERLYING MECHANISMS AMONG INDIVIDUALS IS ONLY BEGINNING TO BE CLARIFIED, BUT THE ESTABLISHMENT OF A FRAMEWORK CAN FACILITATE THE DEVELOPMENT OF AN INTEGRATED UNDERSTANDING OF THE PATHOGENESIS OF ARTHRITIS ACROSS ALL AGES. 2022